High Molecular Weight Kininogen Deficiency

High Molecular Weight Kininogen Deficiency
Apr 7, 2010 6:18pm

A message from Kim Kinney at Clarian:

Hi George, I am giving a case study presentation and one of the studies is about a woman who had a homozygous HMWK (Fitzgerald factor)  deficiency. While we were working her up we read in a reference about the Fletcher factor (PK )  screening test where you incubate patient plasma with PTT reagent that contains either kaolin or silica as the activator. If after a 10-minute vs the usual 3- or 5-minute activation the time corrects, it could be a PK deficiency. Do you know why this happens?

Also, I read that moderately low PK levels are found in most homozygous HK deficient patients. Do you know why that is other then they bind together? Thanks, Kim

Hi, Kim. Love your questions, they gave me another two hours in the books! There are several articles from the 70s and 80s documenting the 10-minute incubation with kaolin or Celite to detect PK deficiency. This does not work with PTT reagents that use ellagic acid as the activator. However, none of the articles even speculate on the mechanism.

I’ve had the notion that the prolonged incubation activates XII and HMWK , subsequently activating XI while bypassing PK , but have no proof. The prolonged incubation does not correct the PTT prolongation associated with XII or HMWK deficiency. See Hattersley PG , Hayse D. The effect of increased contact activation time on the activated partial thromboplastin time. Am J Clin Pathol 1976; 66: 479.

I’ve not seen an association of PK deficiency with HK deficiency, and couldn’t find it in my two favorite references, Colman or Kitchens. Please send me your reference, as I am curious. Meanwhile, maybe one of our participants has the answer. Geo.

4 Comments

A message from Kim Kinney at Clarian:

Hi George, I am giving a case study presentation and one of the studies is about a woman who had a homozygous HMWK (Fitzgerald factor)  deficiency. While we were working her up we read in a reference about the Fletcher factor (PK )  screening test where you incubate patient plasma with PTT reagent that contains either kaolin or silica as the activator. If after a 10-minute vs the usual 3- or 5-minute activation the time corrects, it could be a PK deficiency. Do you know why this happens?

Also, I read that moderately low PK levels are found in most homozygous HK deficient patients. Do you know why that is other then they bind together? Thanks, Kim

Hi, Kim. Love your questions, they gave me another two hours in the books! There are several articles from the 70s and 80s documenting the 10-minute incubation with kaolin or Celite to detect PK deficiency. This does not work with PTT reagents that use ellagic acid as the activator. However, none of the articles even speculate on the mechanism.

I’ve had the notion that the prolonged incubation activates XII and HMWK , subsequently activating XI while bypassing PK , but have no proof. The prolonged incubation does not correct the PTT prolongation associated with XII or HMWK deficiency. See Hattersley PG , Hayse D. The effect of increased contact activation time on the activated partial thromboplastin time. Am J Clin Pathol 1976; 66: 479.

I’ve not seen an association of PK deficiency with HK deficiency, and couldn’t find it in my two favorite references, Colman or Kitchens. Please send me your reference, as I am curious. Meanwhile, maybe one of our participants has the answer. Geo.

By Kjkinney
Apr 7, 2010 6:51am
Thanks George,
Here is my reference: Goodnight SH, Hathaway WE. Disorders of Hemostasis & Thrombosis, A Clinical Guide, 2nd Edition, McGraw-Hill, New York 2001, Chapter 16, p 157.
By George Fritsma
Apr 7, 2010 7:21am
Thanks, Kim. I phoned Dave McGlasson after posting this and he pointed me to articles by Alvin Schmaier, MD, University of Michigan, who has done a lot of work on PK and HK. Schmaier is referenced by Goodnight and Hathaway. It appears that HK assembles on endothelial cell surface receptors and their activates PK. PK in turn activates XII. I'll speculate that without HK present, the inactive form of PK may not get measured in a factor assay.
By Kjkinney
Apr 7, 2010 11:09am
That does make sense. Well, I have done more digging on the good ol' internet and found some more info about the Fletcher Factor test..still not sure I get it. I quoted below.

" However, a good tip-off to the diagnosis of PK or HMWK deficiency is that the prolonged APTT is significantly shortened by prolonged preincubation of the patient’s plasma with kaolin and cephalin (for example, preincubation for 10–20 minutes instead of the standard 1 minute), which allows sufficient auto-activation of factor XII, thus bypassing the requirement of PK or HMWK." I still don't see how that distinguishes PK from HMWK...
By Mdrejka
Apr 24, 2013 9:14am
George,
Regarding prolonged activation times-I'm getting frustrated. I had more success with playing with this 15 years ago! However, this is what our lab does for PK and HMWK. First we do a straight (silica)PTT mixing study with incubation. When it corrects without prolonging and all other factors are normal we go to a specific PTT mix using known PK deficient then HMWK deficient plasma. When we find correction with one and non-correction (bingo!)with the other mix and we know which deficiency we have. Do you see any flaws in this rational?
P.S. We do not quantify these two factors because of maintenance on assays that would be rarely used.

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